The long term goal of this study is to determine the functions of two novel genes, attractin (Atrn) and mahogunin (Mgrn1), in age-related neurodegeneration. Atrn and Mgrn1, which were originally identified to be in the same genetic pathways to regulate pigmentation, have been shown to cause age-related neurodegeneration. Loss-of-function mutations of Atrn or Mgrn1 result in similar widespread neurological abnormalities including neuronal cell death, hypomyelination and vacuolation, accompanied by body tremor. A progressive loss of substantia nigra neurons has been observed in spontaneous mutant rats with Atrn deficiency. Atrn encodes a transmembrane protein, while Mgrn1 encodes an intracellular E3 ubiquitin ligase, which is an important component in the ubiquitin-proteasome system (UPS). Phenotypic rescue studies in mice suggest that Mgrn1 might lie genetically downstream of Atrn in the regulation of pigmentation. However, whether this is also true for the neurodegeneration phenotype, how Atrn and Mgrn1 cross-talk, and whether they represent two components in the same intracellular signaling pathway are unknown. The abnormality of the UPS is one of the common features shared by several known neurodegeneration disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS). It raises a question of whether Atrn and Mgrn1 are involved in the pathogenesis of these known age-related neurodegenerative diseases. Our preliminary data provided evidence that these two genes play a role in the survival of dopaminergic neuronal cells. We found that reducing the endogenous expression level of Atrn or Mgrn1 exacerbates, whereas overexpressing Atrn or Mgrn1 protects against, the dopaminergic neuronal cell death caused by neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) or lactacystin (a proteasome inhibitor) in vitro (preliminary data). Both neurotoxins induce Parkinson-like syndromes in animal models. Furthermore, for the first time, we demonstrated that vast majority of the dopamine neurons (>95%) in the substantia nigra of mice express both Atrn and Mgrn1 (preliminary data), providing the anatomical and molecular basis for potential direct influences of Atrn and Mgrn1 on the nigrostriatal dopamine system. We hypothesize that transgenic expression of Atrn protects dopamine neurons in the substantia nigra and that Mgrn1 functions as a downstream molecule mediating Atrn's actions on the survival of dopaminergic neurons. To test this hypothesis, we have two specific aims: Specific Aim 1. Determine whether transgenic expression of Atrn in mice protects the dopamine neurons in the SN using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Specific Aim 2. Determine whether Atrn regulates dopaminergic neuronal survival via Mgrn1. [unreadable] Identifying the genes that are involved in the pathogenesis and mechanisms of neurodegenerative diseases will help us to develop new treatment strategies for these diseases. Based upon our preliminary data, we propose to determine the protective role of Atrn and Mgrn1 both in vitro and in vivo using a PD disease model. The studies will lead to possible new mechanisms of the pathogenesis and therapeutic interventions for both PD and other neurodegenerative diseases. [unreadable] [unreadable] [unreadable]